Known genetic risk factors for breast cancer account for only ~30% of the familial risk of the disease (so-called 'missing heritability') with common variants (frequency >10%) revealed through genome-wide association studies (GWAS) explaining one-third of this percentage. A large fraction of familial risk is likely due to variants that are less common (1-10%) or rare (<1%); a space of genetic variation that has yet to comprehensively explored in relationship with breast cancer risk. In this application, we propose to undertake a large-scale collaborative effort to uncover genetic predictors of breast cancer in women at high familial/genetic risk. For this effort, we have assembled an international team of investigators with experience in breast cancer research who are eager and willing to pool resources, specimens and data from their established studies, to search for novel and less common risk variants for this major cancer. In Aim 1, we propose to conduct a well-powered genome-wide association study (with 80% power to detect a relative risk of 1.5 or more, or 0.67 or less, for a variant with frequency as low as 1%). In stage 1, we will genotype 5 million SNPs for 3,000 breast cancer cases at increased familial/genetic risk, based on having a strong family history of the disease, and 3,000 controls of European ancestry. In stage 2, we will follow-up the 500 most significant associations using an additional 17,000 breast cancer cases and 17,000 controls of European ancestry. Novel validated risk variants will be examined in African American, Latino and Japanese samples, as well as in relationship with breast cancer tumor subtypes. A second Aim of this study will be to conduct a hypothesis generating GWAS analysis of estrogen receptor positive and estrogen receptor negative breast cancer in women at high familial/genetic risk in search of risk variants that are specific for these tumor subtypes. We will also estimate the amount of familial aggregation (polygenic variance; heritability) explained by all known risk variants (Aim 3), including those discovered in Aim 1, using population-based case family studies with detailed information about family history and DNAs from relatives from the Breast Cancer Family Registry (BCFR). Our goal is to improve upon the comprehensive risk model BOADICEA for estimating a woman's lifetime risk of breast cancer based on her genetic, family history and epidemiologic profile. We expect this work to significantly advance knowledge of the etiology of breast cancer and to guide the development of future preventive, early detection, prognostic and even therapeutic measures that will have wide clinical and public health utility.